A cetylcysteine for the prevention of C ontrast-induced nephropa T hy (ACT) Trial:

1. Acetylcysteine for the prevention of Contrast-induced nephropaThy (ACT) Trial: A Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography The ACT Trial Investigators Presenter: Otavio Berwanger (MD; PhD) Chair - SteeringCommitte Sponsor: Ministry of Health-Brazil

2. Presenter Disclosure Information Presenter: Otavio Berwanger Acetylcysteine for the Prevention of Contrast-Induced nephropaThy (ACT) Trial: a Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography FINANCIAL DISCLOSURE: None to declare

3. Why do WeNeed a NewAcetylcysteine Trial ? THE PROBLEM Contrast-inducednephropathyis associatedwithmortalityandprolongedhospitalization. The incidence in patientswithriskfactors (such as renal failure, diabetes, age > 70 y) varies between 9% and 38%. ONE POTENTIAL SOLUTION Acetylcysteine (anantioxidant) represents a safe, non-expensive , easy to administer, andwidelyavailabledrug THE EVIDENCE Lowquality (fewtrialswithallocation concealment, blinding, and ITT analysis) Lowstatisticalpower (mediantrialsize = 80 patients) Uncertaineffectsonclinicalendpoints Lackofstandardizationofacetylcysteine dose/schemeandco-interventions

4. The ACT Trial • Design: Academic,PragmaticRandomizedMulticenter Trial ofAcetylcysteine versus Placebo for thePreventionof Renal Outcomes • Preventionof Bias: • Concealedallocation (central web-basedrandomization) andIntention-to-treatanalysis • Blindingofpatients, investigators, caregivers, andoutcomeassessors • Quality control: on-site monitoring + central statistical checking + e-CRF • Trial Size: 2,308* patients from 46 hospitals in Brazil recruited between September 2008 and July 2010 * Original Target Sample Size: 2300, considering incidence of CIN =15%, 30% relative risk reduction (RRR), with 90% statistical power, and two-tailed alpha of 5%

5. Trial Organization Trial Steering Committe Otavio Berwanger Alexandre Biasi Cavalcanti Amanda Sousa Celso Amodeo J. Eduardo Sousa Leda D. Lotaif Project Office Data Management/e-CRF Research Institute HCorCarlos Cardoso Alexandre Biasi Cavalcanti Andre L.A. Firmino Anna Maria Buehler Dalmo Silva Mariana Carballo Paulo J. Soares Alessandra Kodama Adailton Mendes Eliana Santucci Jose Lobato Centres Top Recruiting Sites: 46 Institutions in BrazilHospital Bandeirantes (Sao Paulo) Beneficiencia Portuguesa (Sao Paulo) Hospital P.S. Mat. Santa Lucia (Minas Gerais) Instituto de Cardiologia (StaCatarina)

6. 2,308 Patients undergoing an angiographic procedure with at least one of the following risk factors: Age > 70 years; Chronic Renal Failure; Diabetes Mellitus; Heart Failure or LVEF <0.45; Shock Concealed Randomization Acetylcysteine 1200mg Orally Twice Daily for 2 Doses Before and 2 Doses After Procedure Matching Placebo ITT ITT Primary Endpoint: Contrast-induced nephropathy (CIN) (≥ 25% elevation of serum creatinine above baseline 48h-96h after angiography) Secondary Endpoints: Total mortality, CV mortality, Need for dialysis, Doubling of serum creatinine, Side effects

7. (1172) Placebo (1136) Acetylcysteine Age – yr 68.0  10.4 68.1  10.4 Female sex 38.0% 39.3% Patients fulfilling inclusion criteria 15.4% 16.0% Chronic Renal Failure* Diabetes mellitus 61.2% 59.7% Heart failure 9.9% 9.2% Shock 0.3% 0.2% Acute coronary syndrome 35.8% 35.1% 61.4 (45.2 to 83.3) 60.2 (45.4 to 84.5) Glomerular filtration rate Baseline Characteristics Coronary diagnostic angiography 67.1% 68.7% 28.5% 30.1% Percutaneous coronary intervention * Serum creatinine >1.5mg/dL (stable measurements)

8. Compliance and Co-interventions (1172) Placebo (1136) Acetylcysteine Adherence to study drug • 1st dose 99.0% 99.4% 2nd dose 97.6% 97.3% 3rddose 96.4% 96.1% 4th dose 95.6% 94.9% Hydration before procedure 47.1% 47.5% NaCl 0.9% - 1ml/Kg/h ≥ 6 h NaCl 0.9% - any scheme 94.3% 94.3% 5.1% Bicarbonate 4.6% Hydration after procedure NaCl 0.9% - 1ml/Kg/h ≥ 6 h 52.3% 54.8% NaCl 0.9% - any scheme 71.2% 74.1% 28.8% 28.5% Bicarbonate Contrast High/low/iso-osmolar (%) 22.0/ 75.0 / 3.0 22.9 / 74.3 / 2.9 Volume (mL) 100 (70 to 130) 100 (70 to 130)

9. Results Acetylcysteine (N=1172) Placebo (N=1136) PrimaryEndpoint

10. Results Acetylcysteine (N=1172) Placebo (N=1136) PrimaryEndpoint

11. ClinicalOutcomes at 30 days Acetylcysteine (N=1172) Placebo (N=1136) Mortality or need for dialysis

12. ClinicalOutcomes at 30 days Acetylcysteine (N=1172) Placebo (N=1136) Mortality or need for dialysis

13. Side Effects Placebo n (%) Acetylcysteine P value n (%) Adverse events 89 (7.6) 0.61 80 (7.0) 8 (0.7) 15 (1.2) Nausea 0.12 4 (0.3) Vomiting 14 (1.2) 0.01 25 (2.1) Angina 14 (1.2) 0.09 Fatigue 13 (1.1) 19 (1.6) 0.33 Diarrhea 10 (0.9) 7 (0.6) 0.43 Serious adverse events * 25 (2.2) 15 (1.3) 0.09 Includes: stroke, pneumonia, sepsis, acute pulmonary edema - (Less then 10 events per endpoint)

14. SubgroupAnalysis Also no difference for subgroups: Creatinine ≥ 2mg/dl Time of measurement of post-procedure creatinine

15. Updated Meta-Analysis All criteria adequate * = Allocation concealment, double-blind and ITT

16. MainConclusions Largest acetylcysteine randomized trial conducted to date. Acetylcysteine does not reduce the short-term risk of CIN nor other clinically relevant outcomes (30 days) even among the higher risk subgroups. These results are consistent with meta-analysis of previous smaller high quality trials (zero heterogeneity). These results may help to inform clinical practice and to update current guidelines.